Inflammation is the result of a complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. It is part of an attempt by a patient to remove the injurious stimuli, as well as to initiate the healing process for the tissue. Due to an increased blood flow that accompanies this healing process, there is a rapid delivery of immune system cells thereby causing the patient to experience the swelling and redness that are associated with inflammation.
An inflammatory response may be initiated at the site of injury by endothelial cells that produce molecules that attract and detain inflammatory cells (e.g., myeloid cells such as neutrophils, eosinophils, and basophils). The inflammatory cells are then transported through the endothelial barrier into the surrounding tissue. The resulting accumulation of inflammatory cells, in particular neutrophils, is followed by generation of toxic oxygen particles and release of neutrophil granules that contain acid hydrolases and degradative enzymes such as proteases, elastase, and collagenase, which contribute to local tissue breakdown and inflammation. Neutrophils can also release chemoattractants and complement activators that amplify the inflammation.
Although the inflammatory response can play a role in the healing process by destroying, diluting, and isolating injurious agents as well as stimulating repair of the affected tissue, inflammatory responses can also be harmful, and indeed life-threatening. Five symptoms often characterize the inflammatory response: pain, redness, heat, swelling, and loss of function. For example, inflammation may result in leakage of plasma from the blood vessels. Although this leakage can have beneficial effects, it can also cause pain, and when uncontrolled lead to loss of function and, in severe cases, death. Anaphylactic shock, arthritis, and gout are among the conditions that are characterized by uncontrolled or inappropriate inflammation.
In certain situations, after injury or infection heals, proinflammatory activity persists. This, in turn, leaves sensory nerves carrying pain information to the brain to remain sensitized in the absence of injury or infection. Consequently, the patient experiences pain.
One particularly painful disease is sciatica. Sciatica is a chronic disease that often can be very debilitating and may take a terrible toll on those with the disease as well as their families, friends and caregivers. Sciatica is a very painful disease associated with the sciatic nerve which runs from the lower part of the spinal cord (the lumbar region), down the back of the leg and to the foot. Sciatica generally begins with a herniated disc, which later leads to local immune system activation. The herniated disc also may damage the nerve root by pinching or compressing it, leading to additional immune system activation in the area. There has been considerable interest in developing effective treatments for this painful disease, yet to date current treatments of sciatica are only partially effective.
Inflammation also has an immunological component, which can cause problems particularly in heterologous tissue or organ transplants. Transplant rejection occurs when the immune system of the recipient of a transplant attacks or rejects the tissue (or organ) that has been transplanted.
To prevent rejection, one strategy that is employed by the medical community to reduce the likelihood of transplant rejection is to use donated tissues from related individuals. A second strategy, which may be used in combination with the first strategy, is to use chemical compositions that suppress the immunological response that may lead to rejection of the donated tissue.
One compound that is known to reduce inflammation and/or immunological rejection of transplanted tissue is fluocinolone, which in its acetonide form (C24H30F2O6) has been administered topically as a cream in connection with hand transplants. It may also be referred to as 4b, 12-Difluoro-6b-glycoloyl-5-hydroxy-4-a,6a,8,8-tetramethyl-4a,4b,5,6,6a,6b,9a, 10, 10a, 10b,11,12-dodecahydro-2H-naphtho[2′,1′:4,5]indeno[1,2-d][1,3]dioxol-2-one or 6α-,9α-Difluoro-16α-hydroxyprednisolone 16,17-acetonide.
However, to date there is an unmet need to be able to reduce inflammation, pain, and/or immunological rejection utilizing sustained release fluocinolone.